title: TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres.
abstract: Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku's association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vital for NHEJ. We show that Ku's interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 α5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku's ability to synapse telomere ends.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Ribes-Zamora
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Indiviglio
authors.forename: Ivana
authors.initials: I
authors.lastname: Mihalek
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Williams
authors.forename: Alison A
authors.initials: AA
authors.lastname: Bertuch
mesh_terms: D034961:Antigens, Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D008958:Models, Molecular; D055503:Protein Multimerization; D011995:Recombination, Genetic; D016615:Telomere / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen